title: Catalysis of Na+ permeation in the bacterial sodium channel Na(V)Ab.
abstract: Determination of a high-resolution 3D structure of voltage-gated sodium channel Na(V)Ab opens the way to elucidating the mechanism of ion conductance and selectivity. To examine permeation of Na(+) through the selectivity filter of the channel, we performed large-scale molecular dynamics simulations of Na(V)Ab in an explicit, hydrated lipid bilayer at 0 mV in 150 mM NaCl, for a total simulation time of 21.6 μs. Although the cytoplasmic end of the pore is closed, reversible influx and efflux of Na(+) through the selectivity filter occurred spontaneously during simulations, leading to equilibrium movement of Na(+) between the extracellular medium and the central cavity of the channel. Analysis of Na(+) dynamics reveals a knock-on mechanism of ion permeation characterized by alternating occupancy of the channel by 2 and 3 Na(+) ions, with a computed rate of translocation of (6 ± 1) × 10(6) ions⋅s(-1) that is consistent with expectations from electrophysiological studies. The binding of Na(+) is intimately coupled to conformational isomerization of the four E177 side chains lining the extracellular end of the selectivity filter. The reciprocal coordination of variable numbers of Na(+) ions and carboxylate groups leads to their condensation into ionic clusters of variable charge and spatial arrangement. Structural fluctuations of these ionic clusters result in a myriad of ion binding modes and foster a highly degenerate, liquid-like energy landscape propitious to Na(+) diffusion. By stabilizing multiple ionic occupancy states while helping Na(+) ions diffuse within the selectivity filter, the conformational flexibility of E177 side chains underpins the knock-on mechanism of Na(+) permeation.
authors.affiliation: Molecular Structure and Function, Hospital for Sick Children, Toronto, ON, Canada M5G 1X8.
authors.forename: Nilmadhab
authors.initials: N
authors.lastname: Chakrabarti
authors.forename: Christopher
authors.initials: C
authors.lastname: Ing
authors.forename: Jian
authors.initials: J
authors.lastname: Payandeh
authors.forename: Ning
authors.initials: N
authors.lastname: Zheng
authors.forename: William A
authors.initials: WA
authors.lastname: Catterall
authors.forename: Régis
authors.initials: R
authors.lastname: Pomès
mesh_terms: D002384:Catalysis; D017136:Ion Transport; D007700:Kinetics; D012964:Sodium / Q000378:metabolism*; D015222:Sodium Channels / Q000378:metabolism*
chemical_list: D015222:Sodium Channels; D012964:Sodium